International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

A26. Comparative Genome Analysis of the Pax1 and Pax9 Genes

Fabio Santagati, Chikara Kokubu, Bettina Wilm, Kenji Imai

GSF-National Research Center for Environment and Health, Institute of Mammalian Genetics, 85764 Neuherberg, Germany

Pax1 and Pax9 are two of the nine members of the Pax gene family, which encode transcription factors characterized by a highly conserved DNA-binding domain, the paired box. Pax1 and Pax9 are highly homologous, and they are expressed in similar and overlapping domains of embryonic tissues including the sclerotome of somites, the pharyngeal pouch endoderm and its derivatives, and developing limb mesenchymes. By gene targeting experiments, it has been shown that Pax1 and Pax9 exert synergistic functions during vertebral column development.

In order to elucidate so far unknown regulatory mechanisms of Pax1 and Pax9, we have undertaken a comparative genomics approach in the mouse, human and Fugu genomes. We report the conserved physical linkage between two pairs of paralogous genes: Pax1 and Nkx2-2, and Pax9 and Nkx2-9 in the vertebrate genomes. Notably, all of them are known to be Shh-responsible. Possible implications of this conserved synteny will be discussed in a context of their regulation.

In parallel, we have investigated two deletion mutations of Pax1, Pax1un-ex and Pax1Un-s, which significantly differ in the mode of inheritance and in the severity of their phenotypes. The recessive Pax1un-ex mutation can be regarded as a natural null allele, whereas the semidominant Pax1Un-s mutation shows significantly more severe defects than the targeted Pax1-null allele, indicating the involvement of a gene or genes nearby Pax1 in the Pax1Un-s mutation. In the present study we have defined and analyzed their deletion intervals to understand the molecular basis of the Pax1Un-s mutation. Our results indicate the deletion intervals to be 60 kb and 125 kb in Pax1un-ex and Pax1Un-s, respectively. We will discuss about the second gene(s) affected by the Pax1Un-s mutation as potential modifiers of Pax1.

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